1. Field of the Invention
The invention relates to processes for continuously measuring the concentration of an analyte in tissue, as well as to devices for said measurements and to devices which make such measurements and respond by administering an active substance to a patient whose tissue was analyzed.
2. Description of the Prior Art
In medical science, both human and veterinary, a very important criterion for diagnosis and or treatment is the level of certain substances in blood and/or tissue.
The substances of interest (hereinafter referred to as analytes) can be of a wide variety. They can be intermediates or endproducts in metabolism, hormones or hormoneprecursors, antibodies or antigens, pathogens, drugs, etc.
In a number of cases it will be important to keep a continuous check on levels of an analyte in blood and/or tissue.
The analyte which heretofore has been the foremost subject in continuous measurements is glucose in patients suffering from diabetes mellitus.
Though the invention is explained more in detail using glucose as a model system, it is by no means restricted in its use exclusively to that kind of measurement.
Processes and devices for continuously measuring glucose concentrations in (subcutaneous) tissue are known.
It has also been proposed to couple such a measuring device to an insulin pump which can be worn by or implanted in a patient and which then reacts to changes in the blood and/or tissue glucose level.
Generally speaking, these methods and devices are used for patients for whom the classical methods of injecting insulin once or twice a day cannot provide a satisfactory regulation of the glucose (blood) level in the patient.
However, if a "patient friendly" device for measuring analytes such as glucose and dosing a substance such as insulin in reaction to changes in the analyte concentration could be designed, the use of such devices could be far more widespread then this particular group of patients.
Several research groups are involved in designing glucose sensors. One of those research groups is the group of Shichiri of the "First Department of medicine, at the university of Osaka, Japan. This group succeeded [see Diabetologia 24 (1983) 179-184; Biomed. Blochim. Acta 43 (1984), 561-568; Diabetes Care 9 (1986) 298-301] in developing a glucose sensor capable of measuring the glucose concentration in subcutaneous tissue for three days. The small needle-type glucose sensor consists of a platinum electrode covered with immobilized enzyme glucose oxidase. In the reaction of glucose with oxygen in the presence of the enzyme H.sub.2 O.sub.2 is released which can be measured by this electrode and correlates with the amount of glucose present.
In vitro the electrode gives a current of 1.2.+-.0.4 nA in a 5.5 mmol/1 glucose solution. The current is linear with the glucose concentrations, and the time required to obtain 90% of the plateau value is 16.2.+-.6.2 sec.
In first instance, subcutaneous measurements were carried out in dogs, the response showing a delay of 5-15 minutes compared to the direct measurement in blood. The sensitivity of the electrode gradually decreases to 57.4.+-.7% of the initial value after 96 hours measurement. This loss of signal, mainly due to the rapid breakdown of the enzyme, means that the subcutaneously inserted sensor must be replaced at least every three days.
Eventually, Shichiri developed a completely wearable artificial endocrine pancreas (12.times.15.times.6 cm, 400 g) consisting of the sensor, a microcomputer which calculates the required infusion rate of insulin, and a dual-syringe driving system. This apparatus is capable of controlling the blood glucose concentration in depancreatized dogs for three days. Shichiri then proceeded to measurement in subcutaneous tissue of diabetics. The subcutaneously measured glucose values are, on average, 10% lower than those of blood, but there is a good correlation between the two values in the range of from 60 to 400 mg/dl glucose. Then, patients suffering from diabetes were provided with the complete artificial pancreas, using a self-developed subcutaneous insulin infusion algorithm. Only one representative patient in which the glucose was controlled by the sensor for two days is mentioned.
Another research group is directed by M. Kessler of the Institute for Physiology and Cardiology of the University of Erlangen-Nuremberg. The glucose sensor they developed [Hepatogastroenterol. 31 (1984) 285-288] also operates through an enzymatic conversion of glucose by means of glucose oxidase, followed by measuring the resulting H.sub.2 O.sub.2 using an electrode with a gold anode covered with three membranes. A dialysis membrane permeable to glucose, gases and inorganic ions but impermeable to larger molecules, such as proteins, serves as a selector. In the next layer there is an enzyme membrane functioning as a kind of reaction space. Contained therein is the immobilized enzyme glucose oxidase. A sealing lipophilic membrane with incorporated proton carrier molecules is closest to the gold anode. In the presence of the enzyme the glucose diffusing through the dialysis membrane reacts with oxygen, thus forming H.sub.2 O.sub.2. The H.sub.2 O.sub.2 is oxidized at the gold anode so as to form two protons. These are eliminated by the proton carriers. With this sensor Kessler carried out measurements in the peritoneum of anesthetized rats. He found a good correlation between the glucose values measured in the peritoneum and the real blood glucose values. Dimensions of the electrode are not mentioned, but an electrode suitable for implantation in human beings is not yet available.
A. Muller and P. Abel of the Zentralinstitut fur Diabetes "Gerhardt Katsch" from Karlsberg (GDR) (Prof. U. Fischer) also have a glucose oxidase/H.sub.2 O.sub.2 sensor available [Biomed. Blochim. Acta 43 (1984) 577-584; Biomed. Biochim. Acta 45 (1986) 769-777]. Again the immobilized enzyme is attached to the electrode (Pt) surface. The electrode is covered by respectively a hydrophobic and a hydrophilic membrane as a selector for the glucose. After an initial unstable period of 24 hours this electrode gives a stable signal, i.e., a current of 0.02-6.8 nA, depending on the glucose concentration. It is 7 cm in length and has a diameter of 2-4 mm. The electrode was implanted in 6 dogs and the glucose was measured. The ratio between glucose concentrations in blood and in tissue then varies from 33 to 70%. Besides this large variation, failures occur frequently so that a good calibration is not possible.
All the glucose sensors hitherto discussed that have already reached the experimental in vivo stage are based on a system with immobilized enzyme glucose oxidase on an electrode. This has the advantage that the electrode can be miniaturized and readily implanted in whole. However, an important drawback is that under those conditions the enzyme stability is limited and consequently frequent replacement (3-4 days) of the electrode is necessary. Another requirement in the technique of immobilization is that each electrode must be calibrated individually and that it takes several hours to a day before the electrode can give a stable signal.
In European Patent Application No. 88908397.8 a device is disclosed which, like the devices of the invention does not use an implanted electrode, but uses an implant of a hollow fiber, which is suitable for microdialysis.
This device however, requires a reservoir of perfusion fluid and a reservoir for fluids hollow fiber. In other words it is not a closed circuit and both reservoirs need to be changed frequently.